Pathophysiology Of Anemia In Chronic Disease: The Central Role Of Inflammation And Hepcidin
Subtleties of Definition
The definition of anemia caused by chronic diseases was finally established around 1960, when several larger-scale studies related to infections were conducted. Many authors agree that the main causes of these anemias, accounting for approximately 75% of cases, are infection and inflammation, including immune connective tissue diseases and neoplasms, which are not always easy to diagnose and should be suspected when anemia is detected.
The causes of these anemias may include long-lasting infectious diseases such as infective endocarditis, chronic heart failure, chronic kidney disease, especially in dialysis patients, osteomyelitis, hepatitis B and C, and AIDS. Inflammatory anemia may also be caused by intestinal diseases such as Crohn’s disease and ulcerative colitis. In oncology, the most severe inflammatory anemias occur in patients with Hodgkin’s disease, lymphoma, and those undergoing chemotherapy. It is also frequently diagnosed in patients with liver cirrhosis.
Anemia in chronic diseases is caused by immune mechanisms. Cytokines released by reticuloendothelial cells and lymphocytes induce changes in iron metabolism, proliferation and differentiation of erythroid precursors, erythropoietin production, and the lifespan of red blood cells. For this reason, anemia in chronic diseases is also referred to as inflammatory anemia.
Inflammatory anemia is usually mild to moderate, and hemoglobin (Hgb) levels are rarely lower than 80 mg/L. Biochemical testing typically reveals low iron concentration in blood serum despite adequate iron reserves in the body. Transferrin concentration in blood serum is also reduced, although this is considered a late sign because transferrin has a significantly longer half-life (about 8 days) compared with iron (approximately 1.5 hours). Red blood cells are usually normal in size and contain a normal Hgb concentration, but their number in the blood is reduced, resulting in normocytic normochromic anemia. In some cases, especially during prolonged inflammatory diseases, red blood cells may become smaller, leading to reduced Hgb concentration.
Anemia of critical illness presents with similar characteristics, but in patients with infection, sepsis, or other inflammatory diseases treated in intensive care units, it may develop within a few days. In such cases, anemia is aggravated by frequent diagnostic phlebotomies and increased gastrointestinal blood loss.
Senile anemia is a chronic condition similar to inflammatory anemia, but it occurs in older individuals without specific predisposing diseases. Its prevalence increases with age, and detailed studies often reveal elevated C-reactive protein (CRP) or other inflammatory biomarkers.
Anemia associated with chronic kidney disease is often attributed to erythropoietin deficiency, but studies indicate that the pathogenesis of anemia in chronic kidney disease is considerably more complex and only partially overlaps with mechanisms involved in inflammatory anemia. For example, renal anemia develops in chronic kidney failure when creatinine concentration in the blood is—
Diagnostic Challenges
The diagnosis of anemia associated with inflammatory diseases is based on the evaluation of clinical signs and laboratory parameters. Because anemia of chronic disease progresses slowly and is usually not severe according to published data, clinical symptoms are often minimal and nonspecific. Clinical manifestations primarily reflect the underlying disease, such as infection, inflammation, oncological disease, chronic kidney disease, or heart failure, thereby overshadowing the symptoms of anemia itself.
Clinical symptoms of anemia are related to tissue hypoxia. The most commonly observed symptoms include weakness, syncope, irritability, headache, pallor, dyspnea, and chest pain. In more severe cases, thirst, tachycardia, orthostatic hypotension, and tachypnea may occur. Hepatomegaly and/or splenomegaly are sometimes detected, while neurological examination may reveal symptoms of peripheral neuropathy.
Laboratory diagnosis of anemia caused by chronic diseases is performed by excluding other causes of anemia, as there are no laboratory parameters specific exclusively to this pathology. Diagnostic tests include Hgb concentration, erythrocyte and reticulocyte counts, hematocrit, serum iron and ferritin concentration, and transferrin saturation.
Patients with this type of anemia typically have low Hgb levels, decreased or normal reticulocyte counts, and reduced iron concentration, while ferritin concentration remains normal or elevated. This reflects increased iron accumulation and retention within the reticuloendothelial system, as ferritin is a marker of iron reserves.
Traditionally, the gold standard for diagnosing inflammatory anemia was the identification of decreased blood iron concentration (hypoferrimia) or low transferrin saturation despite the presence of Prussian blue staining in bone marrow macrophages detected through myelogram analysis. However, this method has been criticized not only because bone marrow sampling is invasive, but also because interpretation of the findings may vary considerably between specialists.
Studies have shown that iron therapy may lead to iron deposition of questionable quality within the bone marrow, which may later be inadequately utilized in patients who remain iron deficient. Consequently, this method has largely been replaced by serum ferritin determination.
Low serum ferritin concentration (less than 15 ng/mL in the general population, although some laboratories apply age- and sex-specific reference ranges) is considered a highly specific sign of iron deficiency, with the rare exception of genetic L-ferritin deficiency. Such findings effectively rule out inflammatory anemia by indicating the absence of iron reserves in the body. Inflammatory anemia is diagnosed when anemia and hypoferrimia occur without decreased ferritin concentration.
Ferritin concentration increases in the presence of inflammation. It is important to note that ferritin originates from macrophages, where its synthesis rises because of iron sequestration processes associated with inflammation. Iron deficiency is considered to coexist with anemia of chronic disease when ferritin concentration does not increase proportionally to the intensity of inflammation. Serum ferritin may also increase because of tissue damage, particularly in cases of liver injury.
In clinical practice, determining a very low ferritin threshold may be difficult because patients with elevated serum ferritin concentration can still respond positively to intravenous iron therapy, including increases in Hgb concentration. Therefore, the lower limit of serum ferritin may be better assessed using additional indicators of iron deficiency that are less affected by inflammation, particularly soluble transferrin receptors.
However, these studies are not standardized, and their diagnostic value remains uncertain. When clinically significant anemia is detected and iron deficiency is suspected in patients with anemia of chronic disease, intravenous iron therapy may be justified as a therapeutic approach. Modern intravenous iron preparations are generally considered safe, but risk-benefit assessment should include the possibility of rare adverse reactions and the potential exacerbation of existing or occult infectious processes.
Prevalence
There are no detailed statistics on the prevalence of inflammatory disease anemia. It is broadly estimated that the aging population and the high frequency of chronic infections and inflammatory disorders worldwide place inflammatory disease anemia second among all types of anemia, after iron-deficiency anemia. This situation may change as iron-deficiency anemia becomes more effectively treated.
For example, the prevalence of anemia ranges from approximately 10% in patients with moderate chronic heart failure (CHF) to more than 50% in patients with severe CHF. Reduced Hgb concentration in patients with CHF is particularly harmful because it further decreases tissue oxygen supply, increases systolic volume, and intensifies cardiac workload. This may lead to exhaustion, increased left ventricular mass and dilation, myocardial ischemia, and progression of heart failure symptoms.
Pathophysiology
Key principles: • slightly shortened red blood cell survival due to increased destruction; • hypoferrimia, cytokine-stimulated hepcidin increase, and iron-restricted erythropoiesis; • suppression of erythropoiesis due to the direct effect of bone marrow cytokines; • inflammatory effects on erythropoietin production and renal hepcidin secretion.
Chronic disease anemia is caused by a prolonged inflammatory process during which activated reticuloendothelial cells and released cytokines disrupt iron homeostasis, impair proliferation of erythroid progenitor cells, worsen erythropoietin production, shorten the lifespan of red blood cells, and ultimately reduce Hgb synthesis.
Erythropoiesis may be disrupted in several ways, including infection-related conditions such as hepatitis C, malaria, or HIV, as well as infiltration of bone marrow by tumor cells. Tumor cells stimulate the production of inflammatory cytokines and free radicals that damage erythroid progenitor cells. In addition, the condition may be aggravated by episodes of bleeding, vitamin deficiencies such as cobalamin or folic acid deficiency, hypersplenism, autoimmune hemolysis, renal insufficiency, radiotherapy, and chemotherapy.
In anemia caused by chronic diseases, cytokines secreted by reticuloendothelial cells disrupt iron metabolism, resulting in increased iron sequestration and accumulation within reticuloendothelial cells. Cytokines stimulate the immune system to utilize more iron, while immune cells break down red blood cells and absorb the iron they contain. During this process, structural changes occur in immune cells, reducing their ability to release iron. As a result, iron accumulates in macrophages, does not adequately reach the bone marrow, and cannot be effectively used for Hgb synthesis, leading to iron-restricted erythropoiesis.
Another inflammatory mediator, hepcidin, which is produced in the liver, inhibits intestinal iron absorption. Consequently, increased hepcidin levels reduce Hgb production. Under the influence of inflammatory cytokines, erythropoietin production decreases, or the response to this hormone becomes impaired.
The impaired response is associated not only with the effect of pro-inflammatory cytokines on proliferating erythroid precursors, but also with inhibition of erythropoietin receptor function in these cells. Erythropoietin stimulates erythrocyte and Hgb production and regulates erythroid cell proliferation. Therefore, weakening of erythropoietin activity contributes to anemia development.
A separate subtype of this anemia is associated with chronic kidney disease and kidney failure, where erythropoietin deficiency plays a major role. The antiproliferative effects of uremic toxins are also important in the pathogenesis of anemia. In addition, patients undergoing hemodialysis may develop erythropoietin deficiency because greater amounts may be removed during dialysis procedures.
As mentioned previously, oncological diseases are among the most common causes of chronic anemia. Impaired iron metabolism and suppressed erythropoiesis are among the earliest signs of cancer-related anemia. In malignant disease, the lifespan of red blood cells decreases, while the bone marrow is unable to sufficiently increase erythropoiesis or release iron from aging erythrocytes phagocytosed by bone marrow macrophages, resulting in an iron reutilization defect.
The hypoproliferative state associated with tumor-related anemia is linked to reduced erythropoietin production and impaired bone marrow responsiveness to the hormone. Inadequate erythropoietin production is associated with increased tumor cytokine production. Several cytokines, including TNF-alpha, IL-1, IL-6, interferon-gamma, transforming growth factor beta, and EPO, are involved in suppressing erythropoiesis and impairing iron metabolism.
In vitro studies have shown that tumor necrosis factor (TNF-alpha) and interleukin-1 (IL-1) inhibit mRNA synthesis. These findings suggest that the hypoproliferative response may serve as an indirect marker of cytokine activity. Therefore, anemia in patients with oncological diseases may be characterized as a cytokine-related syndrome in which multiple cytokines interact to suppress erythropoiesis and disrupt iron metabolism.
Treatment Options
In most cases, worsening anemia is associated with progression of the chronic disease responsible for its development. Therefore, the primary treatment goal is adequate management of the underlying disease. Anemia itself is treated with blood component transfusions, iron and folic acid supplementation, and erythropoietic agents.
The goal of anemia treatment in patients with chronic diseases is to achieve correction of anemia to an Hgb level of approximately 120 g/L, particularly in patients older than 65 years and in those with additional risk factors such as coronary heart disease or chronic lung or kidney disease. This Hgb level helps ensure adequate tissue oxygenation and improves quality of life, especially in patients undergoing dialysis or chemotherapy.
Blood component transfusion is widely used as a rapid and effective therapeutic measure. Red blood cell transfusions are particularly useful in severe anemia. However, iron therapy in anemia associated with chronic diseases remains controversial.
It is known that iron-saturated macrophages lose some ability to phagocytize microorganisms and altered cells. Furthermore, iron therapy in the setting of prolonged immune activation may promote the formation of highly toxic hydroxyl radicals, potentially leading to tissue damage, endothelial dysfunction, and increased risk of serious cardiovascular events.
On the other hand, iron therapy may also provide clinical benefits. Treatment with iron preparations suppresses TNF-alpha formation and reduces disease activity in conditions such as rheumatoid arthritis and end-stage kidney disease. In addition to absolute iron deficiency, patients with anemia caused by chronic diseases may develop functional iron deficiency because intensive erythropoiesis occurs during treatment with erythropoietic agents. In patients undergoing chemotherapy or hemodialysis, parenteral iron may improve the response to erythropoietic therapy.
Erythropoietic agents are approved for the treatment of inflammatory anemia in patients with oncological diseases undergoing chemotherapy, chronic kidney disease, HIV infection, or treatment with myelosuppressive drugs. When erythropoietin is used to treat chronic disease-related anemia, a favorable response is observed in approximately 25% of patients with myelodysplastic syndrome, 80% of patients with multiple myeloma, and up to 95% of patients with rheumatoid arthritis or chronic kidney disease.
Poor response to erythropoietic therapy is associated with elevated levels of pro-inflammatory cytokines and impaired iron transfer from macrophages.
The main treatment approaches include: • treatment of the underlying disease; • targeted treatment for severe anemia or disturbances in daily functioning; • erythropoiesis-stimulating agents with or without intravenous iron therapy, although these are not approved as specific treatment; • experimental and not fully investigated therapies involving new erythropoiesis-stimulating agents such as epoetin alfa and darbepoetin alfa, anti-cytokine therapies, and agents targeting the hepcidin-ferroportin pathway.
A new treatment approach involving pentoxifylline has been widely discussed. Although pentoxifylline itself is not a new drug, clinical studies evaluating its effects in patients with chronic diseases have revealed a previously underrecognized property. Research has shown that pentoxifylline not only improves blood flow and reduces blood viscosity, platelet adhesion, and aggregation, but may also increase Hgb concentration. Effective correction of anemia improves survival in patients with chronic diseases and contributes to better disease outcomes. In patients with chronic heart failure, it may also improve cardiac function. Therefore, pentoxifylline may help achieve better therapeutic results.
Pentoxifylline is a methylxanthine derivative that improves blood flow and inhibits platelet function, thereby enhancing tissue circulation and the delivery of oxygen and nutrients. Oxygenation improves most significantly in areas affected by severe ischemia. The beneficial effect of pentoxifylline on blood rheological properties is associated with reduced whole blood and plasma viscosity, which results from intensified fibrinolysis or decreased fibrinogen synthesis and concentration. These effects are influenced by increased concentrations of adenosine triphosphate, cyclic adenosine monophosphate, and other cyclic nucleotides in erythrocytes.
In recent years, studies have demonstrated that pentoxifylline not only reduces blood viscosity and improves circulation, but also modulates the immune response. This discovery has attracted considerable attention. Pentoxifylline has been shown to inhibit TNF-alpha, which stimulates neutrophil adhesion to vessel walls. In altered blood vessels, thrombi may form, resulting in vascular narrowing and impaired tissue perfusion. Therefore, the anti-inflammatory effects of pentoxifylline are also considered clinically important.
Thus, pentoxifylline:
- increases erythrocyte deformability;
- inhibits platelet aggregation;
- stimulates prostacyclin synthesis, thereby further suppressing platelet aggregation;
- reduces elevated fibrinogen concentration;
- decreases increased blood viscosity;
- inhibits leukocyte adhesion to the endothelium;
- suppresses leukocyte activation and endothelial damage;
- moderately dilates blood vessels.
The identified indications for pentoxifylline use as a microcirculation regulator include:
- atherosclerotic, diabetic, inflammatory, or functional peripheral arterial and venous circulation disorders;
- intermittent claudication, rest pain, diabetic angiopathy, and obliterative endarteritis;
- trophic disorders such as post-thrombotic syndrome, leg ulcers, and gangrene;
- angioneuropathies;
- acute and chronic retinal and choroidal circulation disorders;
- impaired cerebral blood flow, including ischemic and post-stroke conditions;
- vascular-origin disorders of inner ear function, including hearing impairment and sudden hearing loss.
Pentoxifylline is contraindicated in patients after recent myocardial infarction, during episodes of severe bleeding, in cases of extensive retinal hemorrhage, or in individuals with hypersensitivity to pentoxifylline or other methylxanthines.
Conclusions
- Anemia caused by chronic diseases is the second most common type of anemia and usually develops because of immune system activation or bone marrow suppression.
- Chronic heart failure, chronic kidney failure, and oncological diseases are among the most common chronic conditions associated with anemia.
- Inflammatory anemia is caused by reduced blood iron levels associated with hepcidin activity, cytokine-induced suppression of erythropoiesis, and shortened red blood cell lifespan.
- Treatment with erythropoiesis-stimulating agents and/or intravenous iron is required only in selected cases.
- The positive effects of pentoxifylline on blood rheological properties have already been demonstrated. Recent findings regarding its potential to increase blood Hgb concentration provide new perspectives for the treatment of inflammatory anemia.
